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Investigating mechanisms of chemoresistance in triple-negative breast cancer

Award Number: R01CA255742
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/11/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Investigating mechanisms of chemoresistance in triple-negative breast cancer - Project Summary Chemotherapy remains the standard of care for patients with triple-negative breast cancer (TNBC), which affects 20% of patients with breast cancer. However, 50% of patients with localized TNBC treated with neoadjuvant chemotherapy display residual cancer burden after treatment and up to 25% of patients who receive this treatment will suffer metastatic recurrence within five years. The poor association between chemotherapy and patient outcome emphasizes two major problems for TNBC patients: chemoresistance, where tumor cells within the local environment are protected and do not die in response to chemotherapy, and chemotherapy-induced metastasis, where chemotherapy-induced changes in tumor intrinsic properties and the tumor microenvironment drive invasion which leads to recurrence. Previous studies have demonstrated that cell migration and extracellular matrix (ECM) remodeling are associated with chemoresistant TNBC. The goal of this proposal is to understand the mechanisms by which the ECM contributes to chemoresistance and chemotherapy-induced metastasis in TNBC. We provide preliminary data that individual proteins upregulated in TNBC tumors drive resistance to chemotherapy drug Paclitaxel and that expression of Cathepsin B (CTSB), a protease which degrades these ECM proteins into small fragments, protects against the development of chemoresistance. We will dissect the mechanism by which the protease CTSB and the ECM proteins it degrades influence response to Paclitaxel in TNBC and whether these fragments can be used to track and target chemoresistance in vivo. We have also found that chemotherapy treatment leads to changes in the ECM composition of mammary tumors. Specifically, Paclitaxel treatment leads to an increased abundance of Collagen IV, an ECM protein which promote invasion and metastasis in TNBC. Our goal is to determine the cell types that secrete ECM proteins such as Collagen IV after chemotherapy treatment, determine the contribution of these ECM proteins to chemotherapy-induced metastasis, and whether these pathways can be targeted to prevent the development of recurrence. Upon successful completion of the proposed research, our contribution is expected to be an understanding of how ECM proteins upregulated in TNBC tumors contribute to chemoresistance and how chemotherapy alters the ECM to promote recurrence and metastatic dissemination. These contributions will be significant because all TNBC patients receive chemotherapy and metastatic recurrence is a current unmet clinical need. Results from these studies will provide novel conceptual insights on mechanisms of chemoresistance and chemotherapy-induced metastasis and will allow us to develop new strategies to track, predict and overcome chemoresistance in TNBC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $347,067 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	80 GEORGE ST	MEDFORD	MA	02155	MIDDLESEX	USA	Cancer Biology Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	000	4	12/23/2024	NON-COMPETING CONTINUATION	$312,360
2025	2025	TRUSTEES OF TUFTS COLLEGE	80 GEORGE ST	MEDFORD	MA	02155	MIDDLESEX	USA	Cancer Biology Research	002	4	5/29/2025	NON-COMPETING CONTINUATION	$34,707
														Subtotal = $347,067

Issue Date FY: 2024 ( Subtotal = $407,385 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	003	3	4/11/2024	NON-COMPETING CONTINUATION	$0
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	001	3	12/19/2023	SUPPLEMENT FOR EXPANSION	$77,670
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	000	3	12/15/2023	NON-COMPETING CONTINUATION	$312,360
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	004	3	4/18/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	005	3	4/19/2024	NON-COMPETING CONTINUATION	$17,355
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	002	3	3/4/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $407,385

Issue Date FY: 2023 ( Subtotal = $389,028 )
2023	2023	TRUSTEES OF TUFTS COLLEGE INC	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	000	2	2/15/2023	NON-COMPETING CONTINUATION	$340,125
2023	2023	TRUSTEES OF TUFTS COLLEGE INC	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	001	2	9/1/2023	SUPPLEMENT FOR EXPANSION	$48,903
														Subtotal = $389,028

Issue Date FY: 2022 ( Subtotal = $347,192 )
2022	2022	TRUSTEES OF TUFTS COLLEGE INC	169 HOLLAND ST FL 3	SOMERVILLE	MA	02144	MIDDLESEX	USA	Cancer Biology Research	000	1	1/11/2022	NEW	$347,192
														Subtotal = $347,192

Grand Total All Awards = $1,490,672

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Investigating mechanisms of chemoresistance in triple-negative breast cancer

Award Number: R01CA255742

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/11/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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